tbuckley/cabot-search huggingface dataset:
Evaluating the utility of ctDNA in detecting residual cancer and predicting recurrence in patients with serous ovarian cancer.
Authors: Mohammad R. Akbari, Jie Wei Zhu, Fabian Wong, Agata Szymiczek, Gabrielle Ene, Shiyu Zhang, Taymaa May, Steven A Narod, Joanne Kotsopoulos
Journal: Journal of Clinical Oncology (2022)

e17588 Background: Ovarian cancer remains the most fatal gynecological malignancy. Patients who have no visible residual disease after surgical resection have a relatively good prognosis. Among these patients, those who later succumb to their cancer are believed to harbour non-detectable cancer cells in the peritoneal cavity after treatment which later lead to recurrence. Analyzing circulating tumour DNA (ctDNA) in the blood may offer a sensitive method to detect occult (non-visible) residual disease after surgery and to predict disease recurrence. We proposed to determine the proportion of ovarian cancer patients with and without visible residual disease documented after surgery who had detectable ctDNA from their primary tumour in their blood and to evaluate if the presence of ctDNA is associated with survival. Methods: We included biological samples and clinical information from 48 women diagnosed with high-grade serous ovarian cancer. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue, and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. The plasma sample was collected after surgery and before initiating chemotherapy. We sequenced DNA samples for a panel of 59 breast and ovarian cancer driver genes. DNA variants in matched germline and tumour DNAs were compared to determine tumour specific variants (TSVs) and cfDNA was searched for TSVs to identify the presence of ctDNA in the plasma. The Kaplan-Meier method was used to estimate overall and recurrence-free survival according to the presence or absence of ctDNA. Results: We found TSVs in 47 patients that were used for detecting ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Among the 31 (68.1%) pateints with no visible residual disease, 24 (77.4%) patients had detectable ctDNA. Of those with no visible residual disease, those patients with detectable ctDNA in post-surgery samples had a higher mortality risk compared to those without detectable ctDNA (HR 2.32; 95% CI: 0.67-8.05), although this difference was not statistically significant (p = 0.18). Conclusions: These findings suggest potential clinical utility in ctDNA to improve upon surgical classification of the residual disease status and a potential predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings.
Detection of high-grade glioma clusters: Spatial case-control study using EMR data from 2010-2021.
Authors: Sonikpreet Aulakh, Wesley Kimble, Brian Hendricks
Journal: Journal of Clinical Oncology (2022)

e14016 Background: High-grade gliomas (HGGs), like Glioblastomas (GBMs), are the most common malignant intracranial tumors with dismal prognosis. Rural areas have higher HGG related mortality and lesser research advancements. The objective of this study was to identify zip codes with disproportionate risk of HGGs compared to other brain malignancies. Methods: Patients’ electronic health data for this case-control study was extracted from West Virginia University Hospital Systems, 2010-2021. HGG cases were defined using diagnoses codes ICD10-C71 and ICD9-191 (excluding low grade gliomas). The control group was defined by using diagnoses codes ICD10-D32, C79.3, C71 (excluding HGG cases) and ICD9-225.2, 225.4, 198.3, 191 (excluding HGG cases). Controls were exact matched four controls to every case based upon patient five-year age categories and gender. Clustering was assessed globally through difference in Ripley’s-K between cases and controls; and locally using scan statistics. Results: The locations of HGGs and other brain tumors were clustered in the northern and northeastern regions of WV. Global cluster analyses detected statistically significant dispersion of HGG cases compared to our control group. Local cluster analysis identified multi-zip code cluster of HGG patients in northeastern WV between 2010-2021. The average relative risk of HGG compared to other brain malignancies was 1.25, indicating a 25% increase in risk of HGGs compared to other brain cancers within this region. While the local cluster was not statistically significant, the zip code level estimates of relative risk within the cluster ranged from 0.00 to 5.01. This indicated that certain zip codes within the cluster had five times the risk of HGGs compared to non-HGG brain malignancies relative to zip codes outside of the cluster. Conclusions: Findings indicate community level disparities in risk of HGGs relative to other brain malignancies. Additionally, results suggest that HGG cases are seen across the state at a more dispersed pattern than for non-HGG related brain tumors. These overall spatial trends could potentially be attributable to differences in clinical practice, access to care, or social determinants of health throughout WV. Spatial multivariable modeling techniques are needed to identify the specific neighborhood level factors associated with disproportionate patterns of risk identified for WV HGG patients.
Patient preferences for second-line treatment options in diffuse large B-cell lymphoma: A discrete choice experiment.
Authors: Kelly Birch, Kevin Chiu, James Baumgardner, Julia Snider, Sally West Wade, Gunjan L. Shah
Journal: Journal of Clinical Oncology (2022)

e19558 Background: Standard of care (SOC) treatment in second-line (2L) large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL), involves salvage chemotherapy followed by autologous hematopoietic cell transplant (AHCT) for those with chemo-sensitive disease. However, many patients do not respond adequately to chemotherapy or are otherwise ineligible for AHCT. Chimeric antigen receptor T-cell (CAR T) therapy is a promising 2L therapy for LBCL that differs from SOC agents in terms of mechanism of action, therapeutic benefit, and safety profile. Given these differences, this discrete choice experiment (DCE) quantified 2L treatment preferences among patients with DLBCL. Methods: We conducted an online DCE with patients with DLBCL residing in the United States (US) and Europe (United Kingdom, France, Italy, Germany, and Spain). Attributes of 2L treatments were parameterized based on clinical trial data and included the probability (percent of patients) of surviving one year after treatment, the change in survival rate from one to three years, the risks of severe cytokine release syndrome (CRS) and neurological events, the risk of severe infection, and expected time until the patient’s functioning would return to pre-treatment levels. A willingness-to-accept measure was used to assess how much of an increase in one-year survival was needed for a patient to accept elevated risks of severe CRS and neurological events, which can be associated with CAR T treatment. Results: A total of 224 patients were included in the analysis (US: 105; Europe: 119). The mean age of respondents was 50 years (range 34 - 76); 74% were male, and 94% were actively receiving cancer treatment. Patients considered the probability of surviving one year after treatment to be the most influential treatment attribute, followed by risk of severe CRS/neurological events. The third most influential attribute was the change in probability of survival for three years post-treatment for US patients and time needed to return to pre-treatment functioning for European patients. The willingness-to-accept calculation found that patients required a 13-14 percentage point increase in the probability of surviving one year to accept a 28% risk of a serious neurological event and a 13% risk of serious CRS. Conclusions: Patients with DLBCL showed their willingness to accept increased risks of CRS and neurological events to achieve a greater probability of survival. This preference tradeoff (efficacy over risk of adverse events) has been shown previously for lymphoma patients. Patients also valued a quicker return to baseline functioning, which is notable given recent data on the quicker recovery of quality of life with CAR T compared with SOC. These patient preferences provide important context for 2L LBCL treatment decisions, and may lead to shared decision-making that reflects both clinical and patient priorities.
Growing financial burden from targeted oral anticancer medicines among Medicare beneficiaries with cancer.
Authors: Meng Li, Kai-Ping Eric Liao, I-Wen Pan, Ya-Chen Tina Shih
Journal: Journal of Clinical Oncology (2022)

6504 Background: The rapidly rising costs of targeted oral anticancer medicines (TOAMs) raise concerns over their affordability. Our goal was to examine recent trends in the uptake of TOAMs among cancer patients with Medicare Part D, the share of TOAM users who reached catastrophic coverage, and the annual spending on TOAMs in the catastrophic phase. Methods: Using the 5% SEER-Medicare, we included patients aged 65 and older who had one primary cancer diagnosis between 2011 and 2016. We included person-years where patients were enrolled in a Part D plan for the entire year, did not receive the Low-Income Subsidy (LIS) at any time of the year, and received anticancer systemic therapies. We estimated the trends in the share of patients who used TOAMs, the percentage of TOAM users reaching catastrophic coverage, and the total and patient out-of-pocket spending on TOAMs in the catastrophic phase in a year. Results: From 2011 to 2016, the uptake of TOAMs among our study population increased from 3.6% to 8.9%. The percentage of non-LIS TOAM users who reached catastrophic coverage increased from 54.6% to 60.3%. Among those who reached the catastrophic phase, mean total gross spending on TOAMs in the catastrophic phase increased from $16,074 to $64,233 and mean patient out-of-pocket spending from $596 to $2,549. The mean 30-day total spending increased from $4,011 to $8,857, and the mean 30-day out-of-pocket spending from $154 to $328. Conclusions: The high and growing burden from TOAMs highlighted the need for reining in drug prices and capping out-of-pocket spending.
Artificial Intelligence and Machine Learning Technologies in Cancer Care: Addressing Disparities, Bias, and Data Diversity
Authors: Irene Dankwa-Mullan, Dilhan Weeraratne
Journal: Cancer Discovery (2022)

Summary: Artificial intelligence (AI) and machine learning (ML) technologies have not only tremendous potential to augment clinical decision-making and enhance quality care and precision medicine efforts, but also the potential to worsen existing health disparities without a thoughtful, transparent, and inclusive approach that includes addressing bias in their design and implementation along the cancer discovery and care continuum. We discuss applications of AI/ML tools in cancer and provide recommendations for addressing and mitigating potential bias with AI and ML technologies while promoting cancer health equity.
IMMU-08. Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: efficacy, safety, biomarker, and pharmacokinetic results from Checkmate 908
Authors: Ira J Dunkel, Kenneth Cohen, Nicholas K Foreman, Darren Hargrave, Alvaro Lassaletta, Nicolas André, Jordan R Hansford, Tim Hassall, Matthias Eyrich, Sridharan Gururangan, Ute Bartels, Amar Gajjar, Lisa Howell, Deepti Warad, Misena Pacius, Rachel Tam, Yu Wang, Li Zhu, François Doz
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in pediatric patients with high-grade CNS malignancies, consistent with available historical data. The safety profiles were manageable.
AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in <i>EGFR</i>-mutant lung adenocarcinoma.
Authors: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Jacklynn V. Egger, Umesh Bhanot, Juan Qiu, Elisa de Stanchina, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Triparna Sen, Charles M. Rudin
Journal: Journal of Clinical Oncology (2022)

e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.
Progress in Gastroparesis - A Narrative Review of the Work of the Gastroparesis Clinical Research Consortium
Authors: Pankaj J Pasricha, Madhusudan Grover, Katherine P Yates, Thomas L Abell, Kenneth L Koch, Richard W McCallum, Irene Sarosiek, Cheryl E Bernard, Braden Kuo, Robert Bulat, Robert J Shulman, Bruno P Chumpitazi, James Tonascia, Laura A Miriel, Laura A Wilson, Mark L Van Natta, Emily Mitchell, Frank Hamilton, Gianrico Farrugia, Henry P Parkman
Journal: Clinical Gastroenterology and Hepatology (2022)
Protein, fat, and animal food intakes and premature aging in adult survivors of childhood cancer: St. Jude Lifetime (SJLIFE) cohort.
Authors: Yikyung Park, AnnaLynn Williams, Emily R Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie L. Robison, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2022)

10055 Background: Childhood cancer survivors are a growing population who appear to be at higher risk for premature aging and age-related chronic health conditions than their peers with no history of cancer. Diet affects many hallmarks of aging, such as inflammation, metabolic dysfunctions, and molecular and epigenetic changes, leading to impairment in physical and cognitive functions and premature death. High consumption of animal foods that are high in protein and fat increase risk for many age-related chronic diseases. However, some studies found protein intake was beneficial for physical frailty in elderly and cancer survivors. Methods: Adult survivors (&gt; = 18 years old) of childhood cancer survivors enrolled in the SJLIFE Cohort between 2007 and 2017 completed a 110-item food frequency questionnaire at study entry (n = 3,322). Survivors’ sociodemographic, cancer, cancer treatments, and medical history data were abstracted from medical records. Health conditions self-reported after cancer diagnosis were clinically validated. Premature aging was assessed using the Deficit Accumulation Index (DAI) based on 45 aging-related health conditions. DAI is categorized into low (&lt; 0.2), medium (0.2-0.34) and high (&gt; 0.35) aging risk groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multinomial logistic regressions adjusting for potential confounders. Results: The average age of survivors at baseline was 31 years. Approximately half of the survivors were women, and 82% were white, non-Hispanic. 20% and 8% of survivors were at medium and high risk for aging, respectively. Survivors at high risk for aging tended to be female, smokers, have low socioeconomic status, and received radiation therapy to head and neck, chest, spine or abdomen compared to those at low aging risk. Higher protein intake was associated with a less risk of premature aging (OR = 0.74, 95% CI: 0.58-0.95 for high aging risk group; OR = 0.91, 95% CI: 0.78-1.07 for medium aging risk group, per increment of 5% of total energy intake). On the other hand, higher fat intake was related to an increased risk of premature aging (OR = 1.14, 95% CI: 1.01-1.29 for high aging risk group; OR = 0.99, 95% CI: 0.91-1.08 for medium aging risk group, per increment of 5% of total energy intake). However, substituting monounsaturated fat for other types of fat was associated with a lower risk of premature aging (OR = 0.81 95% CI: 0.70-0.95 for high aging risk group). Red meat (OR = 1.11, 95% CI: 0.87-1.42 for high aging risk group) and dairy intake (OR = 0.99, 95% CI: 0.72-1.38 for high aging risk group) was not related to risk of premature aging. Conclusions: Consuming protein and fat from healthy foods may lower the risk of premature aging in childhood cancer survivors.
Comprehensive characterization and functional implications of mesenchymal stem cell-related genes in pancancer: A new horizon for immunotherapy.
Authors: Chaozhi Tang, Jiakang Ma, Xueting Wang, Fang Lei, Kaining Lu, Wentao Zhang, Yuyan Zhu, Xudong Yao, Bin Yang
Journal: Journal of Clinical Oncology (2022)

e14577 Background: Accumulated evidence demonstrates that mesenchymal stem cells (MSCs) contribute to tissue regeneration, tumor progression, chemotherapy resistance, and mediate tumor immune escape by modulating the stroma and immunity of the tumor microenvironment. However, little is known about the role of MSCs in cancer patients receiving immunotherapy. Therefore, we investigated the comprehensive characterization of MSC-related genes and their functional implications in pan-cancer immunotherapy. Methods: We performed a pan-cancer analysis of 59 MSC-related genes, which was used to calculate an MSC score with single sample gene set enrichment analysis. Multivariate Cox regression analysis was performed to identify a potential independent prognostic marker for cancer. TIDE algorithm and neural network were utilized to assess the predictive accuracy of MSC-related genes for immunotherapy. Results: MSC-related gene expression showed significant differences inconsistently between normal and tumor samples across the 33 cancer types (p &lt; 0.05). Cox regression analysis suggested that the MSC score is an independent prognostic marker for papillary renal cell carcinoma (TCGA; OS, RFS and DSS, all p &lt; 0.05), mesothelioma (TCGA and GSE29354, OS, all p &lt; 0.05), glioma (TCGA and GSE107850, OS, all p &lt; 0.05), and stomach adenocarcinoma (TCGA, GSE84437, GSE15459, GSE13861 and GSE62254, OS; GSE13861 and GSE62254, RFS; all p &lt; 0.05). The abundance of fibroblasts was also more representative of the MSC score compared to the stromal score. Samples with a high MSC score were predicted to have low responsiveness to immunotherapy, which was validated across seven immune checkpoint therapy datasets (IMvigor210, 27.52% (low) vs 18.12% (high); GSE78220, 64.28% (low) vs 42.86% (high); GSE135222, 30.77% (low) vs 28.57% (high); GSE165252, 36.11% (low) vs 28.57% (high); GSE79671; 38.89% (low) vs 33.33% (high); PRJEB25780, 45.45% (low) vs 8.70% (high); GSE176307, 22.22% (low) vs 13.64% (high)). TIDE algorithm and Neural network demonstrated a good predictive accuracy of MSC-related genes for immunotherapy (CESC, COAD, DLBC, GBM, KIRC, LAML, LIHC, LUAD, LUSC, MESO, OV, PCPG, PRAD, SARC, SKCM, THCA, UCEC, and UCS; all ROC ≥0.9). Conclusions: We characterized the MSC-related genes across multiple cancer types and highlighted their potential as a predictive biomarker for immunotherapy response and prognosis. A prospective clinical trial is warranted to confirm these findings.
Long-acting HIV fusion inhibitor albuvirtide combined with ritonavir-boosted lopinavir for HIV-1-infected patients after failing the first-line antiretroviral therapy: 48-week randomized, controlled, phase 3 non-inferiority TALENT study
Authors: Bin Su, Cheng Yao, Qing-Xia Zhao, Wei-Ping Cai, Min Wang, Hong-Zhou Lu, Ting-Ting Mu, Yuan-Yuan Chen, Li Liu, Hui Wang, Yun He, Yu-Huang Zheng, Ling-Hua Li, Jin-Feng Chen, Jian-Hua Yu, Biao Zhu, Min Zhao, Yong-Tao Sun, Wen-Hui Lun, Yi-Hang Zhang, Hu Wang, Wei Xia, Li-Jun Sun, Li-Li Dai, Tai-Yi Jiang, Mei-Xia Wang, Qing-Shan Zheng, Hai-Yan Peng, Yao Wang, Min Hu, Xia Liu, Rong-Jian Lu, Jian-Hua Hu, Cheng-Chen Sun, Hui Xing, Yi-Ming Shao, Dong Xie, Tong Zhang, Fu-Jie Zhang, Hao Wu
Journal: Journal of Infection (2022)